Screening of genes associated with osteogenesis imperfecta by next-generation sequencing technology and investigation of unknown genes

Osteogenesis imperfecta (OI) is the most common genetic bone disorder characterized by recurrent bone fractures and low bone mass. It is a clinically and genetically heterogeneous disorder. The aim of this study is the screening of mutations in COL1A1/COL1A2 genes; identifying other OI related mutations with OI-specific targeted panel-gene testing. It is also aimed to discover novel genes with whole-exome sequencing (WES) in patients who do not have any mutations in known OI genes. 79 patients diagnosed with OI were included in our study. Mutations and large deletion-duplications in COL1A1/COL1A2 genes were investigated with NGS and MLPA methods, respectively. Targeted panel-gene sequencing specific to OI related genes was performed. To discover novel genes, WES was performed in 10 patients. 47 patients were male and 32 were female. The consanguinity rate was 40,7%. We identified heterozygous mutations in COL1A1/COL1A2 genes in 57% patients and homozygous mutations in recessively inherited genes in 22.8% patients and no mutations were found in 20.2%. In our study, the mutation rate in COL1A1/COL1A2 genes was lower than previously reported patients due to the high ratio of consanguinity and recessively inherited types of disease in our patient group. The variants that truncate COL1A1/COL1A2 protein synthesis (18%) resulted in milder phenotype whereas missense mutations that convert glycine to serin resulted in severe phenotype (20%). Patients with recessive form had severe or moderate phenotype. In conclusion, this study revealed mutation rates among OI patients in our country and has made significant contributions to the algorithm of molecular diagnosis of disease.